title: Retinoic acid inhibits NFATc1 expression and osteoclast differentiation.
abstract: Ingestion of excess vitamin A appears to correlate with an increased fracture risk, an outcome that is likely mediated by retinoic acids (RAs); these are vitamin A metabolites that have dramatic effects on skeletal development. We studied the impacts of RA and isoform-specific RA receptor (RAR) agonists (α, β, and γ) on osteoclast formation (osteoclastogenesis) in two model systems: RAW264.7 cells and murine bone marrow-derived monocytes. The pan-RAR agonists, all-trans and 9-cis RA, inhibited receptor activator of nuclear factor kappa B ligand (RANKL)-mediated osteoclast differentiation in a concentration-dependent manner. Isoform-specific RAR agonists (α, β, and γ) also inhibited osteoclastogenesis, with the RARα agonist producing the most consistent reductions in both osteoclast number and size and total area covered. Inhibition of osteoclastogenesis correlated with reductions in expression, DNA binding, and nuclear abundance of nuclear factor of activated T cells c1 (NFATc1), a transcription factor critical for osteoclastogenesis. The upregulation of three NFATc1-responsive genes, cathepsin K, dendritic cell-specific transmembrane protein and osteoclast-associated receptor were similarly reduced following RA or RAR agonist exposure. These results suggest that RA blocks in vitro RANKL-mediated osteoclastogenesis by decreasing NFATc1 function.
authors.affiliation: Geriatric Research, Education, and Clinical Center and Research Service, Bruce W. Carter Veterans Affairs Healthcare System, Miami, FL 33125, USA. wbalkan@miami.edu
authors.forename: Wayne
authors.initials: W
authors.lastname: Balkan
authors.forename: María
authors.initials: M
authors.lastname: Rodríguez-Gonzalez
authors.forename: Manhui
authors.initials: M
authors.lastname: Pang
authors.forename: Isabel
authors.initials: I
authors.lastname: Fernandez
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Troen
mesh_terms: D000135:Acid Phosphatase / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D056657:Cathepsin K / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D002460:Cell Line; D019295:Computational Biology; D003984:Dibenzazepines / Q000494:pharmacology; D024202:Electrophoretic Mobility Shift Assay; D007527:Isoenzymes / Q000378:metabolism; D051379:Mice; D050778:NFATC Transcription Factors; D010010:Osteoclasts / Q000166:cytology* / Q000187:drug effects*; D010012:Osteogenesis / Q000187:drug effects; D053245:RANK Ligand / Q000494:pharmacology; D018168:Receptors, Retinoic Acid / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071681:Tartrate-Resistant Acid Phosphatase; D014212:Tretinoin / Q000494:pharmacology*
chemical_list: D003984:Dibenzazepines; D007527:Isoenzymes; C104183:LE 540; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D053245:RANK Ligand; D018168:Receptors, Retinoic Acid; D014212:Tretinoin; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase; D056657:Cathepsin K